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Biomedical subjects

Andrew M Davis

Publications and source records attributed to Andrew M Davis.

At least 19 recordsLinked to original sources
PubMed2006

High precision measurements of non-mass-dependent effects in nickel isotopes in meteoritic metal via multicollector ICPMS.

We measured the Ni isotopic composition of metal from a variety of meteorite groups to search for variations in the 60Ni abundance from the decay of the short-lived nuclide 60Fe (t(1/2) = 1.49 My) and for possible nucleosynthetic effects in the other stable isotopes of Ni. We developed a high-yield Ni separation procedure based on a combination of anion and cation exchange chromatography. Nickel isotopes were measured on a single-focusing, multicollector, inductively coupled mass spectrometer (MC-ICPMS). The external precision on the mass-bias-corrected 60Ni/58Ni ratio (+/-0.15 epsilon; 2sigma) is comparable to similar studies using double-focusing MC-ICPMS. We report the first high-precision data for 64Ni, the least abundant Ni isotope, obtained via MC-ICPMS. The external precision on the mass-bias-corrected 64Ni/58Ni ratio (+/-1.5 epsilon; 2sigma) is better than previous studies using thermal ionization mass spectrometry. No resolvable excesses relative to a terrestrial standard in the mass-bias-corrected 60Ni/58Ni ratio were detected in any meteoritic metal samples. However, resolvable deficits in this ratio were measured in the metal from several unequilibrated chondrites, implying a 60Fe/56Fe ratio of approximately 1 x 10(-6) at the time of Fe/Ni fractionation in chondritic metal. A 60Fe/56Fe ratio of (4.6 +/- 3.3) x 10(-7) is inferred at the time of Fe/Ni fractionation on the parent bodies of magmatic iron meteorites and pallasites. No clearly resolvable non-mass-dependent anomalies were detected in the other stable isotopes of Ni in the samples investigated here, indicating that the Ni isotopic composition in the early solar system was homogeneous (at least at the level of precision reported here) at the time of meteoritic metal formation.

Journal Article↗
PubMed2006

Clinical features and outcomes of childhood dilated cardiomyopathy: results from a national population-based study.

BACKGROUND: Despite considerable mortality, population-based prognostic factors for childhood dilated cardiomyopathy are lacking. METHODS AND RESULTS: A population-based cohort study was undertaken of all children in Australia who presented with cardiomyopathy at age 0 to 10 years between January 1, 1987, and December 31, 1996. A single cardiologist analyzed all cardiac investigations, and a single pathologist analyzed histopathological material. There were 184 subjects with dilated cardiomyopathy. Positive viral identification or lymphocytic myocarditis was found in 30 (68.2%) of 44 cases with available early histology and 8 of 9 cases presenting with sudden death. Freedom from death or transplantation was 72% (95% CI, 65% to 78%) 1 year after presentation and 63% (95% CI, 55% to 70%) at 5 years. By proportional hazards regression analysis, risk factors for death or transplantation comprised age >5 years at presentation (hazard ratio 5.6, 95% CI, 2.6 to 12.0), familial dilated cardiomyopathy (hazard ratio, 2.9; 95% CI, 1.5 to 5.6), lower initial fractional shortening z score (hazard ratio per z-score unit, 0.75; 95% CI, 0.65 to 0.87), and failure to increase fractional shortening z score during follow-up (hazard ratio per unit increase, 0.68; 95% CI, 0.58 to 0.79). At follow-up, 78 (44.6%) of 175 cases diagnosed during life have no symptoms and are not taking any cardiac medication. CONCLUSIONS: Early mortality is high in childhood dilated cardiomyopathy, but the clinical status of long-term survivors is good. This population-based study identifies children at risk of adverse events.

Cardiomyopathy, Dilated↗
PubMed2006

In silico human and rat Vss quantitative structure-activity relationship models.

We present herein a QSAR tool enabling an entirely in silico prediction of human and rat steady-state volume of distribution (Vss), to be made prior to chemical synthesis, preceding detailed allometric or mechanistic assessment of Vss. Three different statistical methodologies, Bayesian neural networks (BNN), classification and regression trees (CART), and partial least squares (PLS) were employed to model human (N=199) and rat (N=2086) data sets. The results in prediction of an independent test set show the human model has an r2 of 0.60 and an rms error in prediction of 0.48. The corresponding rat model has an r2 of 0.53 and an rms error in prediction of 0.37, indicating both models could be very useful in the early stages of the drug discovery process. This is the first reported entirely in silico approach to the prediction of rat and human steady-state volume of distribution.

Animals↗
PubMed2006

Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hypertension.

Since September 2001, 7 consecutive patients with childhood idiopathic pulmonary arterial hypertension (IPAH), a rapidly progressive and fatal condition, have been treated with combinations of bosentan, and other therapies (sildenafil/warfarin/epoprostenol), at our institution. Survival and clinical status in these patients were compared with a group of 12 historic control patients who were diagnosed prior to 1997 and received only conventional medical therapy. Survival in the bosentan-treated subjects was better than among historic controls with comparable disease severity (log rank, p = 0.04). Our findings indicate treatment with bosentan permits a delay in IPAH disease progression and, in combination with other therapies, improves survival compared with historic control patients.

Age Factors↗
PubMed2005

The thermodynamics of the partitioning of ionizing molecules between aqueous buffers and phospholipid membranes.

PURPOSE: To study the thermodynamics of partitioning of eight ionising dual D2-recepto beta2-adrenoceptor agonists between vesicles of L-alpha-dimyristoylphosphatidylcholine (DMPC) and aqueous buffers. METHODS: The thermodynamics of partitioning have been studied by isothermal titration calorimetry (ITC). RESULTS: Compounds which are predominantly cationic at pH 7.4 (designated as class 1 compounds) have a more exothermic partitioning than those which are predominantly in the electronically neutral form (designated as class 2 compounds) at pH 7.4, and less positive standard entropies of partitioning. Under acidic conditions (pH 4.0), class compounds 2 (predominantly electronically neutral at pH 7.4) are almost completely cationic and accordingly have a more exothermic partitioning than at pH 7.4. The standard entropies of partitioning also depend on the pH. When the compounds are predominantly cationic, the standard entropy change is less positive (less favourable) than under conditions where the compounds are predominantly electronically neutral. CONCLUSIONS: The observations are consistent with the notion of there being a favourable electrostatic interaction (enthalpically) between the positively charged amino-group of predominantly cationic compounds and the negatively charged phosphate group of the vesicle.

Adrenergic Agonists↗
PubMed2005

Clinical features and outcomes of childhood hypertrophic cardiomyopathy: results from a national population-based study.

BACKGROUND: Population-based studies have provided insight into the natural history of adult hypertrophic cardiomyopathy, but comparable information for affected children is lacking. METHODS AND RESULTS: All Australian children who presented with primary cardiomyopathy at 0 to 10 years of age between January 1, 1987, and December 31, 1996, were enrolled in a longitudinal cohort study. A single cardiologist reviewed serial cardiac investigations on each subject. A total of 80 subjects with hypertrophic cardiomyopathy were identified. An underlying syndromal, genetic, or metabolic condition was identified in 46 subjects (57.5%). There were no cases of sudden death at presentation. Left ventricular outflow tract obstruction was present in 32 subjects (40%); right ventricular outflow obstruction was present in 10 (12.5%). Freedom from death or transplantation was 83% (95% CI, 73 to 90) 5 years after presentation and 76% (95% CI, 62 to 86) 10 years after presentation. By proportional-hazards regression analysis, risk factors for death or transplantation included concentric left ventricular hypertrophy, age at presentation <1 year, lower initial fractional shortening Z score, and increasing left ventricular posterior wall thickness relative to body surface area. At the latest follow-up, 54 of 65 surviving subjects had no symptoms, and 46 were receiving no regular medication. CONCLUSIONS: Syndromal, genetic, and metabolic causes predominate in children with hypertrophic cardiomyopathy. Ventricular outflow tract obstruction is common. The clinical status of long-term survivors is good. This population-based study identifies children with hypertrophic cardiomyopathy who are at risk of adverse events.

Arrhythmias, Cardiac↗
PubMed2005

A rapid computational filter for cytochrome P450 1A2 inhibition potential of compound libraries.

QSAR models for a diverse set of compounds for cytochrome P450 1A2 inhibition have been produced using 4 statistical approaches; partial least squares (PLS), multiple linear regression (MLR), classification and regression trees (CART), and bayesian neural networks (BNN). The models complement one another and have identified the following descriptors as important features for CYP1A2 inhibition; lipophilicity, aromaticity, charge, and the HOMO/LUMO energies. Furthermore all models are global and have been used to predict a diverse independent set of compounds. For the first time in the field of QSAR, the kappa index of agreement has comprehensively been used to assess the overall accuracy of the model's predictive power. The models are statistically significant and can be used as a rapid computational filter for cytochrome P450 1A2 inhibition potential of compound libraries.

Bayes Theorem↗
PubMed2005

Components of successful lead generation.

This review aims to give an overview of current good practice in the prosecution of Lead Generation. It will assess experiences across the field as judged from the contents of the limited number of peer-review disclosures to date. It will also rely heavily on the experiences of the authors from many campaigns within this organisation. Its focus will be on the assembly of an appropriate compound collection for application in High Throughput Screening (HTS), the prosecution of HTS, the profiling of HTS output and, lastly the Hit-to-Lead optimisation of selected HTS output. Excluded from the scope are detailed aspects of library design [1], parallel synthesis [2], virtual library applications [3], virtual screening [4] and fragment screening [5] approaches, all of which have been the subject of recent reviews.

Animals↗
PubMed2004

Clues from Fe isotope variations on the origin of early Archean BIFs from Greenland.

Archean rocks may provide a record of early Earth environments. However, such rocks have often been metamorphosed by high pressure and temperature, which can overprint the signatures of their original formation. Here, we show that the early Archean banded rocks from Isua, Akilia, and Innersuartuut, Greenland, are enriched in heavy iron isotopes by 0.1 to 0.5 per mil per atomic mass unit relative to igneous rocks worldwide. The observed enrichments are compatible with the transport, oxidation, and subsequent precipitation of ferrous iron emanating from hydrothermal vents and thus suggest that the original rocks were banded iron formations (BIFs). These variations therefore support a sedimentary origin for the Akilia banded rocks, which represent one of the oldest known occurrences of water-laid deposits on Earth.

Journal Article↗
PubMed2004

Time-related differences in the physical property profiles of oral drugs.

Comparisons of the calculated physicochemical properties of oral drugs launched prior to 1983 (864 drugs) and between 1983 and 2002 (329 drugs) show that mean values of lipophilicity, percent polar surface area and H-bond donor count are the same, suggesting that these are the most important oral druglike physical properties. In contrast, mean values of molecular weight and the numbers of O + N atoms, H-bond acceptors, and rotatable bonds and rings have increased in 1983-2002 drugs (by 13-29%). Analysis of the 1983-2002 oral drugs by therapy area shows that antiinfectives and nervous system drugs have the most extreme physical property profiles. Cardiovascular drugs show increasing molecular weight with year of publication, primarily a consequence of focusing on clinically proven mechanisms, with limited chemical diversity. Drug classes other than antiinfectives show comparable distributions of lipophilicity, suggesting that this property in oral drugs is important irrespective of the drug's target. The results suggest that the balance between polar and nonpolar drug properties is an important, unchanging feature of oral drug molecules.

Administration, Oral↗
PubMed2004

Chromatographic separation and multicollection-ICPMS analysis of iron. Investigating mass-dependent and -independent isotope effects.

A procedure was developed that allows precise determination of Fe isotopic composition. Purification of Fe was achieved by ion chromatography on AG1-X8 strongly basic anion-exchange resin. No isotopic fractionation is associated with column chemistry within 0.02 per thousand /amu at 2sigma. The isotopic composition was measured with a Micromass IsoProbe multicollection inductively coupled plasma hexapole mass spectrometer. The Fe isotopic composition of the Orgueil CI1 carbonaceous chondrite, which best approximates the solar composition, is indistinguishable from that of IRMM-014 (-0.005 +/- 0.017 per thousand /amu). The IRMM-014 reference material is therefore used for normalization of the isotopic ratios. The protocol for analyzing mass-dependent variations is validated by measuring geostandards (IF-G, DTS-2, BCR-2, AGV-2) and heavily fractionated Fe left after vacuum evaporation of molten wüstite (FeO) and solar (MgO-Al(2)O(3)-SiO(2)-CaO-FeO in chondritic proportions) compositions. It is shown that the isotopic composition of Fe during evaporation of FeO follows a Rayleigh distillation with a fractionation factor alpha equal to (m(1)/m(2)()1/2), where m(1) and m(2) are the masses of the considered isotopes. This agrees with earlier measurements and theoretical expectations. The isotopic composition of Fe left after vacuum evaporation of solar composition also follows a Rayleigh distillation but with a fractionation factor (1.013 22 +/- 0.000 67 for the (56)Fe/(54)Fe ratio) that is lower than the square root of the masses (1.018 35). The protocol for analyzing mass-independent variations is validated by measuring terrestrial rocks that are not expected to show departure from mass-dependent fractionation. After internal normalization of the (57)Fe/(54)Fe ratio, the isotopic composition of Fe can be measured accurately with precisions of 0.2epsilon and 0.5epsilon at 2sigma for (56)Fe/(54)Fe and (58)Fe/(54)Fe ratios, respectively (epsilon refers to relative variations in parts per 10 000). For (58)Fe, this precision is an order of magnitude better than what had been achieved before. The method is applied to rocks that could potentially exhibit mass-independent effects, meteorites and Archaean terrestrial samples. The isotopic composition of a 3.8-Ga-old banded iron formation from Isua (IF-G, Greenland), and quartz-pyroxene rocks from Akilia and Innersuartuut (GR91-26 and SM/GR/171770, Greenland) are normal within uncertainties. Similarly, the Orgueil (CI1), Allende (CV3.2), Eagle Station (ESPAL), Brenham (MGPAL), and Old Woman (IIAB) meteorites do not show any mass-independent effect.

Journal Article↗
PubMed2004

Extinct technetium in silicon carbide stardust grains: implications for stellar nucleosynthesis.

The isotopic composition of ruthenium (Ru) in individual presolar silicon carbide (SiC) stardust grains bears the signature of s-process nucleosynthesis in asymptotic giant branch stars, plus an anomaly in 99Ru that is explained by the in situ decay of technetium isotope 99Tc in the grains. This finding, coupled with the observation of Tc spectral lines in certain stars, shows that the majority of presolar SiC grains come from low-mass asymptotic giant branch stars, and that the amount of 99Tc produced in such stars is insufficient to have left a detectable 99Ru anomaly in early solar system materials.

Journal Article↗
PubMed2004

Predictive ADMET studies, the challenges and the opportunities.

Predictive ADMET is the new 'hip' area in drug discovery. The aim is to use large databases of ADMET data associated with structures to build computational models that link structural changes with changes in response, from which compounds with improved properties can be designed and predicted. These databases also provide the means to enable predictions of human ADMET properties to be made from human in vitro and animal in vivo ADMET measurements. Both methods are limited by the amount of data available to build such predictive models, the limitations of modelling methods and our understanding of the systems we wish to model. The current failures, successes and opportunities are reviewed.

Animals↗
PubMed2003

QSAR and the rational design of long-acting dual D2-receptor/beta 2-adrenoceptor agonists.

This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.

Adrenergic beta-Agonists↗
PubMed2003

Application and limitations of X-ray crystallographic data in structure-based ligand and drug design.

Structure-based design usually focuses upon the optimization of ligand affinity. However, successful drug design also requires the optimization of many other properties. The primary source of structural information for protein-ligand complexes is X-ray crystallography. The uncertainties introduced during the derivation of an atomic model from the experimentally observed electron density data are not always appreciated. Uncertainties in the atomic model can have significant consequences when this model is subsequently used as the basis of manual design, docking, scoring, and virtual screening efforts. Docking and scoring algorithms are currently imperfect. A good correlation between observed and calculated binding affinities is usually only observed only when very large ranges of affinity are considered. Errors in the correlation often exceed the range of affinities commonly encountered during lead optimization. Some structure-based design approaches now involve screening libraries by using technologies based on NMR spectroscopy and X-ray crystallography to discover small polar templates, which are used for further optimization. Such compounds are defined as leadlike and are also sought by more traditional high-throughput screening technologies. Structure-based design and HTS technologies show important complementarity and a degree of convergence.

Crystallization↗
PubMed2003

The epidemiology of childhood cardiomyopathy in Australia.

BACKGROUND: The incidence and age distribution of primary cardiomyopathy in children are not well defined. We undertook a population-based, retrospective cohort study in Australia to document the epidemiology of childhood cardiomyopathy. METHODS: We analyzed all cases of primary cardiomyopathy in children who presented between 1987 and 1996 and who were younger than 10 years of age. Children were recruited from multiple sources, and cases of cardiomyopathy were classified according to World Health Organization guidelines. RESULTS: Over the 10-year period, 314 new cases of primary cardiomyopathy were identified, for an annual incidence of 1.24 per 100,000 children younger than 10 years of age (95 percent confidence interval, 1.11 to 1.38). Dilated cardiomyopathy made up 58.6 percent of cases, hypertrophic cardiomyopathy 25.5 percent, restrictive cardiomyopathy 2.5 percent, and left ventricular noncompaction 9.2 percent of cases. The incidence of all types of cardiomyopathy except restrictive declined rapidly after infancy. In 11 cases (3.5 percent), sudden death was the first symptom. There was a male predominance among children with hypertrophic and unclassified cardiomyopathy. Indigenous children had a higher incidence of dilated cardiomyopathy than nonindigenous children (relative risk, 2.67; 95 percent confidence interval, 1.42 to 4.63) and a higher rate of death as the presenting symptom (16.7 percent vs. 2.6 percent, P=0.02). Lymphocytic myocarditis was present in 25 of 62 children with dilated cardiomyopathy (40.3 percent) who underwent cardiac histologic examination within two months after presentation. CONCLUSIONS: Lymphocytic myocarditis and left ventricular noncompaction are important causes of childhood cardiomyopathy in Australia. The timing and severity of presentation in children with cardiomyopathy are related to the type of cardiomyopathy, as well as to genetic and ethnic factors.

Age Distribution↗